The microbial cell envelope is the point of attack of many antimicrobial systems. The purpose of this project is to understand better how some of these surface active antimicrobials work. The long range goals are two fold. 1) Better understanding of how certain systems selectively damage the surface of various cell types with an eye toward designing better agents and improving therapy. 2) Cell surfaces, especially membranes, are still poorly understood; knowledge of the physical and molecular mechanisms of membrane damage may yield important information on membrane structure and function. Specifically we propose continued work in 3 areas which are already underway and productive. 1) To define the determinants of the action of the polyene antibiotics which are incompletely understood, we shall study defined liposomal membranes as well as natural membranes. We think that better parenteral therapy with these compounds is possible. 2) We have suggested a novel mechanism of polymyxin action and new uses for the drug which require definitive proof; again the goal after understanding is the development of agents with similar mechanisms and better pharmacologic properties. 3) With the techniques we have developed we plan to screen for agents which inhibit the virulence factors of gram-negative bacilli such as somatic or O-antigen.